Aldose reductase (AR) is an enzymatic oxidoreduction system (Alditol-NADF oxidoreductase EC 1.1.1.21) which was first described in 1960/H. G. Hers, Biochim, Biophys. Acta 37, 120-6 (1960)/. The protein, with nicotinamide adenine dinucleotide phosphate (NADPH) as co-factor, catalyses the reduction of various aldoses or similar substances (aldehydes). In a well-balanced biological system it participates in a minor metabolic pathway of glucose, which it converts into sorbitol ("sorbitol pathway"). In diabetic hyperglycemia or galactosemia, the availability of an excess of aldose results in increased activity of the "sorbitol pathway". The result is an accumulation of sorbitol or galactitol in various tissues. This accumulation, which results in degeneration of the tissues where it occurs, has been located inter alia at the crystalline lens (diabetic cataract), nerves (neuropathy), endothelial cells (vasculopathy), kidneys (nephropathy), retina (retinopathy) and the .beta. cells of the pancrease (aggravation of diabetes). This degeneration in diabetics can be prevented by blocking this metabolic pathway of glucose.
Diabetes is a common disease which strikes about 4% of the population. It is a chronic, crippling disease. The degenerative complications of this disease are at present the main problem facing diabetes specialists.
The reason is that treatment with hypoglycemiating agents cannot keep glycemia constant at a normal value and consequently cannot completely prevent accumulation of sorbitol in the cells. Any treatment for preventing or correcting these degenerative anomalies will of course have a wide range of application.
Compounds containing a hydantoin nucleus have already been described as inhibitors of aldose reductase.
Belgian PS No. 859 824, for example, describes a series of "spiro-hydantoins", the most active of which is d-6-fluoro-spiro-/chromane-4,4'-imidazolidine/-2',5'-dione (sorbinil).
Other spiro-hydantoins such as spiro-/fluorene-9,4'-imidazolidine/-2',5'-dione are also described in EPA No. 0 092 358.
The applicants have discovered a new class of spiro-fluorene-hydantoin derivatives having a powerful inhibiting effect of aldose reductase "in vivo". These novel compounds are characterised by the presence of well-defined substituents fixed to one or two nitrogen atoms of the hydantoin nucleus, and by the absence of substituents on the fluorenyl group.
It is well known in the literature that, in general, hydantoin-type compounds have numerous disadvantages such as non-negligible toxicity, a teratogenic effect, serious side effects and difficult absorption.
The applicants have discovered that substitution of the hydantoin nucleus of spiro-/fluorene-9,4'-imidazolidine/-2',5'-dione by suitably chosen radicals can yield products free from toxicity or undesirable side-effects. This substitution also yields products having improved physico-chemical characteristics and biological activity compared with the corresponding non-substituted products.
Compared with spiro-fluorene-hydantoins substituted on the fluorenyl group, the products according to the invention are very easy to prepare, by simple non-laborious methods from raw materials which are commercially available or easy to synthesize.
The derivatives according tothe invention correspond to the general formula I: ##STR2## in which: R.sub.1 and R.sub.2, which may or may not be identical, represent:
(a) Hydrogen or PA1 (b) A CH--OR.sub.4 group in which R.sub.3 represents: PA1 R.sub.4 represents: PA1 (a) A straight-chain or branched C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8, C.sub.9 or C.sub.10 alkyl group PA1 (b) A C.sub.5, C.sub.6 or C.sub.7 cycloalkyl group PA1 (c) A straight-chain or branched C.sub.1, C.sub.2, C.sub.3, C.sub.4 or C.sub.5 alkyl group substituted by a radical chosen from among the following group: PA1 (d) A phenyl group or PA1 (e) An --NH--R.sub.6 group in which R.sub.6 represents hydrogen or a straight-chain or branched C.sub.1, C.sub.2, C.sub.3, C.sub.4 alkyl group or a phenyl group PA1 (f) An --O--R.sub.7 group in which R.sub.7 represents a straight-chain or branched C.sub.1, C.sub.2, C.sub.3, C.sub.4 alkyl group or a phenyl or benzyl group, the groups R.sub.1 and R.sub.2 may not simultaneously be hydrogen, and stereoisomers and mixtures thereof and salts of these compounds formed with pharmaceutically useful metals or organic bases.
(1) Hydrogen PA2 (2) A straight-chain or branched C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl group or PA2 (3) A phenyl group, PA2 (1) Hydrogen PA2 (2) A straight-chain or branched C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8, C.sub.9 or C.sub.10 alkyl group, PA2 (3) A C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7 or C.sub.8 cycloalkyl group PA2 (4) A straight-chain or branched C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl group substituted by: PA2 (a) A phenyl or phenoxy group, or PA2 (b) a phenyl or phenoxy group substituted by one or more C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl or C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkoxy radicals are by one or two atoms of fluorine, chlorine or bromine PA2 (5) A phenyl group, substituted if required by one or two C.sub.1, C.sub.2, C.sub.3, C.sub.4 alkyl or C.sub.1, C.sub.2, C.sub.3, C.sub.4 alkoxy radicals or by one or two atoms of fluorine, chlorine or bromine PA2 (6) A ##STR3## group in which R.sub.5 represents: PA2 A C.sub.5, C.sub.6, C.sub.7 cycloalkyl radical, PA2 A phenyl or phenoxy radical, PA2 A phenyl or phenoxy radical substituted by one, two or three straight-chain or branched C.sub.1, C.sub.2, C.sub.3, C.sub.4 alkyl or C.sub.1, C.sub.2, C.sub.3, C.sub.4 alkoxy groups or by one or two atoms of fluorine, chlorine or bromine,
A preferred embodiment of the invention relates to formula I compounds in which R.sub.1 and R.sub.2 represent a group CHR.sub.3 --OR.sub.4 in which R.sub.3 represents hydrogen or a C.sub.1 -C.sub.4 alkyl group and R.sub.4 represents a group --CO--R.sub.5 in which R.sub.5 represents a straight-chain or branched C.sub.1 -C.sub.10 alkyl group or a straight-chain or branched C.sub.5 -C.sub.7 cycloalkyl group or a straight-chain or branched C.sub.1 -C.sub.5 alkyl radical substituted by a C.sub.5 -C.sub.7 cycloalkyl group.
In a preferred class of formula I products, R.sub.1 and/or R.sub.2 represents hydrogen or a group CHR.sub.3 --O--CO--R.sub.5 in which R.sub.3 represents hydrogen or a methyl group and R.sub.5 represents a straight-chain or branched C.sub.1 -C.sub.10 alkyl group with the restriction that R.sub.1 and R.sub.2 do not simultaneously represent hydrogen.
In another preferred class of formula I products, R.sub.1 and R.sub.2 represent the group --CHR.sub.3 --OR.sub.4 in which R.sub.3 represents hydrogen or a C.sub.1 -C.sub.4 alkyl group and R.sub.4 represents the group CO--O--R.sub.7 in which R.sub.7 can be a C.sub.1 -C.sub.4 alkyl group or a phenyl group or a benzyl group.
Another preferred form of the invention relates to formula I derivatives in which R.sub.1 and/or R.sub.2 represents hydrogen or the group CHR.sub.3 --OR.sub.4 in which R.sub.3 represents hydrogen or a C.sub.1 -C.sub.3 alkyl group and R.sub.4 represents hydrogen or a straight-chain or branched C.sub.1 -C.sub.5 alkyl group, with the restriction that R.sub.1 and R.sub.2 do not simultaneously represent hydrogen.
In a very important class of formula I products, R.sub.1 and/or R.sub.2 represent hydrogen or a group CHR.sub.3 --O--R.sub.4 in which R.sub.4 represents a phenyl group substituted if required by one or two methyl or methoxy radicals or by one or two atoms of fluorine, chlorine or bromine, with the restriction that R.sub.1 and R.sub.2 do not simultaneously represent hydrogen.
A particularly important class of products is that in which the compounds correspond to formula I in which R.sub.1 and/or R.sub.2 represent hydrogen or a CHR.sub.3 --OR.sub.4 group in which R.sub.3 represents hydrogen or a C.sub.1 -C.sub.4 alkyl group and R.sub.4 has one of the following values: a straight-chain or branched C.sub.1 -C.sub.10 alkyl or C.sub.3 -C.sub.8 cycloalkyl or C.sub.1 -C.sub.4 alkyl group substituted by a phenyl or phenoxy group also substituted if required, with the restriction that R.sub.1 and R.sub.2 are not simultaneously hydrogen.
Another preferred class of formula I products is that in which R.sub.1 and R.sub.2 represent the group CHR.sub.3 --OR.sub.4 in which R.sub.3 represents hydrogen or a C.sub.1 -C.sub.4 alkyl group and R.sub.4 corresponds to the CO--NH--R.sub.6 group in which R.sub.6 represents hydrogen or a C.sub.1 -C.sub.4 alkyl or phenyl.
Another preferred form of the invention relates to formula I compounds in which R.sub.1 and R.sub.2 represent a CHR.sub.3 --OR.sub.4 group in which R.sub.3 represents hydrogen or a C.sub.1 -C.sub.4 alkyl group and R.sub.4 represents the group CO--R.sub.5 in which R.sub.5 represents a phenyl group or a C.sub.1 -C.sub.5 alkyl group substituted by a phenyl or phenoxy group which are also substituted if required.
A final preferred form of the invention relates to formula I compounds in which R.sub.1 and/or R.sub.2 represent hydrogen or a group CHR.sub.3 --OR.sub.4 in which R.sub.3 represents a phenyl group, with the restriction that R.sub.1 and R.sub.2 are not simultaneously hydrogen.
The products according to the invention comprising one or more centres of asymmetry can be used either in the form of mixtures containing a number of diastereoisomers in any relative proportions, or in the form of the pure diastereoisomers.
Also, pairs of enantiomers may be present in equal (racemic) or unequal proportions.
Finally, the product may be used in the form of the optically pure compound.
The invention also covers pharmaceutical compositions in which the active ingredient is at least one compound having the general formula I or a salt thereof, with an excipient used in galenic pharmacy.
The compositions are prepared suitable for oral, rectal, parenteral or local administration.
They can be solids or liquids or gels and, depending on the method of administration, can be presented in the form of powders, tablets, dragees, coated tablets, capsules, granulates, syrups, suspensions, emulsions, solutions, suppositories or gels.
The compositions may also contain another therapeutic agent having a simiolar or different activity from the products according to the invention.
The products according to the invention can be used for treatment and prevention of complications of diabetes and galactosemia, e.g. neuropathy, cataracts, retinopathy, nephropathy or vasculopathy.
The following are examples of compounds according to the invention:
bis-(1',3'-hydroxymethyl)-spiro-[fluoroene-9,4'-imidazolidine]-2',5'-dione PA0 bis-(1',3'-acetoxymethyl)-spiro-[fluorene-9,4'-imidazolidine]-2',5'-dione PA0 bis-(1',3'-n.octanoyloxymethyl-spiro-[fluorene-9,4'-imidazolidine]-2',5'-di one PA0 bis-(1',3'-ethoxycarbonyloxymethyl)-spiro-[fluorene-9,4'-imidazolidine]-2', 5'-dione PA0 1'-methoxymethyl-spiro-[fluorene-9,4'-imidazolidine]-2',5'-dione PA0 1'-acetoxymethyl-spiro-[fluorene-9,4'-imidazolidine]-2',5'-dione PA0 bis-(1',3'-N-phenylcarbamyloxymethyl)-spiro-[fluorene-9,4'-imidazolidine]-2 ',5'-dione PA0 bis-[1',3'-(4-cyclohexylbutanoyloxymethyl)]-spiro-[fluorene-9,4'-imidazolid ine]-2',5'-dione PA0 1'-[1-(2,2-dimethylpropanoyloxy)ethyl]-spiro-[fluorene-9,4'-imidazolidine]- 2',5'-dione. PA0 bis-(1',3'-propanoyloxymethyl)-spiro-[fluorene-9,4'-imidazolidine]-2',5'-di one.
The compounds according to the invention can be obtained by a method which also forms part of the invention and consists in substituting one or both hydrogen atoms of the hydantoin group of spiro-/fluorene-9,4'-imidazolidine/-2',5'-dione, product II, which can be performed in one or more steps by known methods.
The process is illustrated by diagram 1 hereinafter.
In this and the following diagrams, the spiro-/fluorene-9,4'-imidazolidine/-2',5'-dione group will be represented as follows: ##STR4##
In diagram 1, R.sub.3 and R.sub.4 have the previously-defined values, A represents the group OR.sub.4 or a group which can be converted into group OR.sub.4, e.g. a hydroxyl or C.sub.1 -C.sub.4 alkoxy group, and B represents an atom or radical easily substituted by the group CR.sub.4, e.g. an atom of chlorine, bromine or iodine or an alkylsulphonate or arylsulphonate group such as O-methyl or O-tosyl. ##STR5##
In a first method, formula I compounds can be obtained by substituting compound II by hydroxyalkylation, followed if required by acylation or alkylation. This method is perfectly suitable for preparing monosubstituted formula I derivatives, by choosing appropriate reaction conditions and more particularly controlling the stoichiometric ratio of the reagents (Diagram 2a).
However, this method is particularly important for preparing disubstituted formula I derivatives, since dihydroxyalkylation is easily performed and usually with very high yields (Diagram 2b). ##STR6##
In diagrams 2a and 2b, groups R.sub.3 and B have the previously-defined values and group OH corresponds to one of the values of A in compound III or V in diagram 1.
1.1 The hydantoin nucleus is hydroxyalkylated in conventional manner by reacting spiro-/fluorene-9,4'-imidazolidine/-2',5'-dione (II) with an aldehyde having the formula R.sub.3 --CHO.
In general, compound II is dissolved or suspended in a solvent such as water, if required in the presence of a co-solvent, e.g. an alcohol such as methanol.
The reagent R.sub.3 --CHO is used either as such or dissolved in a suitable solvent. Alternatively, it ca be used in a protected form, e.g. an acetyl having the formula R.sub.3 --CH(OR.sub.13).sub.2 in which R.sub.2 represents a C.sub.1 -C.sub.3 alkyl group, or in the form of a polymer such as paraformaldehyde.
The temperature of the reaction medium is normally chosen between -15.degree. C. and ambient temperature. In the case where R.sub.3 is different from hydrogen, it may be advantageous to carry out the reaction at a higher temperature, even up to the reflux temperature of the reaction medium. The presence of a base or acid will catalyse the reaction.
In order to form disubstituted formula VIII derivatives, hydroxyalkylation is generally carried out using an excess of the aldehyde R.sub.3 --CHO.
On the other hand, when preparing monosubstituted formula VII derivatives, a strictly metered quantity of aldehyde R.sub.3 --CHO is reacted with compound II, usually by continuous addition of small quantities of aldehyde.
The reaction product is isolated by conventional methods such as filtration, decantation or extraction and can be converted into a formula I compound or a formula IV or VI intermediate with or without preliminary purification.
1.2 Formula VII or VIII intermediate products can be converted into a formula I compound, in which R.sub.4 represents the group CO--R.sub.5, by acylation by conventional methods illustrated in Diagrams 3a and 3b hereinafter. ##STR7##
In diagrams 3a and 3b, R.sub.3 and R.sub.5 have the previously specified values and Z is such that the group CO--Z can represent a carboxyolic or alkoxy carbonyl group (--CCOR.sub.8, in which R.sub.8 represents a C.sub.1 -C.sub.4 alkyl radical or a benzyl or alkyl or phenyl radical substituted so as to activate ester IX for the purpose of nucleophilic substitution), an acid halide group (CO--X) in which X represents an atom of fluorine, chlorine, bromine or iodine or an anhydride group (--CO--O--CO--R.sub.9, R.sub.9 being an R.sub.5 group or a C.sub.1 -C.sub.4 alkyl, phenyl or benzyl radical) or an N-carbonylimidazolyl ##STR8## group.
The acylation reagent R.sub.5 --CO--Z(IX) may also represent a cetene having the formula ##STR9## in which R.sub.10 and R.sub.11 are such that the group ##STR10## corresponds to one of the alkyl, cycloalkyl or substituted alkyl groups represented by R.sub.5.
The acylation group R.sub.5 --CO--Z (IX) may also represent a chloroformate having the formula R.sub.7 O--CO--Cl (X) in which R.sub.7 has the previously-defined values.
If, in the reagent R.sub.5 --CO--Z (IX), the group CO--Z is e.g. an acid halide, anhydride or an N-carbonylimidazolyl group or if R.sub.5 --CO--Z represents a cetene or chloroformate, acylation is usually performed by reacting reagent IX with alcohol VII or VIII either in an inert solvent or using one of the reagents as solvent. If the reagent is an acid halide or anhydride or chloroformate, the reaction is preferably performed in the presence of at least one equivalent of a base which can be organic, e.g. triethylamine or pyridine, or inorganic e.g. a carbonate or bicarbonate of an alkali or alkaline earth metal.
Depending on the reactivity of the acylation agent, a stoichiometric or excess quantity is used, and the reaction occurs at a temperature which may vary from below room temperature to the reflux temperature of the reaction medium.
When in reagent R.sub.5 --CO--Z (IX) the CO--Z group is carboxylic or alkoxycarbonyl (--COOR.sub.8), esterification or transesterification can be carried out in numerous ways.
Conventionally, acid IX or ester IX are reacted with alcohol VII or VIII under anhydrous conditions and in the presence of an acid catalyst such as sulphuric acid or para-toluene sulphonic acid or a strongly acid ion-exchange resin. The solvent can be either one of the reagents or an inert solvent. The reaction is advantageously performed with an excess of one of the reagents, the reaction medium being heated.
Another method consists in continuously eliminating the water or alcohol R.sub.8 --OH formed during the reaction, e.g. by distillation or azeotropic distillation using an appropriate solvent. The reaction conditions are similar to those described hereinbefore except that one reagent need not be used in a large excess.
A third method consists in reacting alcohol VII or VIII in an inert solvent and under anhydrous conditions with a stiochiometric quantity of carboxylic acid IX in the presence of a coupling agent such as 1,1'-carbonyldiimidazole or dicyclohexylcarbodiimide.
1.3 Conversion of theintermediate product of formula VII or VIII into a fomula I compound in which R.sub.4 represents a C.sub.1 -C.sub.10 alkyl or a C.sub.3 -C.sub.8 cycloalkyl or a C.sub.1 -C.sub.4 alkyl group substituted by a phenyl or phenoxy group substituted if required as previously mentioned, is performed by alkylation by known methods, illustrated hereinafter in diagrams 4a and 4b. ##STR11##
R.sub.4 has the previously-mentioned values, R.sub.3 represents the previously specified groups and D represents an easily substitutable group, e.g. an atom of chlorine, bromine or iodine or an alkyl or aryl sulphonate or a sulphate easily substituted by alcohol VII or VIII. Alkylation is conventionally brought about by reacting the reagents in a solvent such as acetone or an aliphatic or aromatic hydrocarbon or dimethylformamide or hexamethylphosphortriamide, preferably in the presence of an organic base such as a tertiary amine or pyridine or an inorganic base such as a carbonate or bicarbonate or alkali or alkaline earth metal hydroxide.
The reaction is definitely brought about at the reflux temperature of the reaction medium.
1.4 Conversion of a formula VII or VIII intermediate product into a formula I compound in which R.sub.4 represents a phenyl group substituted if required, is conventionally brought about by converting alcohol VII or VIII into a formula IV or VI intermediate (see diagram 2) which is subsequently converted into a formula I compound by reaction with a phenol or phenolate having the formula R.sub.4 OH or R.sub.4 O.sup.- in which R.sub.4 represents a phenyl group substituted if required as previously defined.
The conversion of alcohol VII or VIII is described hereinafter in Sections 1.5 and 1.6.
1.5 In a variant of the acylation and alkylation processes described in Sections 1.2 to 1.4, the intermediate formula VII or VIII alcohols can be converted into a formula I derivative via an intermediate formula IV or VI product (see diagrams 2a and 2b).
1. 5.1 Intermediates IV or VI in which B represents a halogen atom such as chlorine, bromine or iodine are obtained by well-known methods e.g. by treating alcohol VII or VIII with a halogenation agent such as a halogenated hydracid, e.g. hydrochloric or hydrobromic acid or an inorganic acid halide such as phosphorus tribromide or phosphorus pentachloride or phosphorus trichloride or thionyl chloride or by reaction with a halogen such as bromine or iodine in the presence of red phosphorus (diagrams 5a and 5b). ##STR12##
X represents an atom of chlorine, bromine or iodine. The reaction with a halogenated hydracid is advantageously performed by reflux-heating the reaction medium, if required in an inert solvent such as an aliphatic or aromatic or chlorinated hydrocarbon, the water formed during the reaction being preferably eliminated e.g. by azeotropic distillation with a suitable solvent.
The reaction with an inorganic acid halide or a halogen in the presence of red phosphorus is performed in an inert solvent at a temperature which is usually between ambient temperature and the reflux temperature of the reaction medium and advantageously in the presence of an agent for capturing the halogenated hydracid formed, e.g. an organic or inorganic base such as pyridine, triethylamine or an alkali metal carbonate.
Halogenated compounds XI and XII are isolated by conventional methods such as filtration, distillation or extraction.
The reactions and reaction conditions for this conversion will be chosen so as not to affect the other groups in the molecule.
1.5.2 When group B in the formula IV or VI intermediates represents a sulphonate group, the products are easily obtainable by reacting a formula VII or VIII alcohol with a sulphonyl chloride having the formula R.sub.12 --SO.sub.2 Cl (R.sub.12 representing a C.sub.1 -C.sub.4 alkyl or an aryl group such as p-tolyl) (diagrams 6a and 6b). ##STR13##
The reaction is preferably performed in the presence of an organic base such as pyridine or triethylamine, or an inorganic base such as a carbonate or bicarbonate of an alkali or alkaline earth metal.
The solvent can be an organic base such as pyridine or an inert solvent such as an ether or aliphatic or aromatic hydrocarbon, which may or may not be chlorinated.
The reaction is normally brought about at ambient temperature or by moderately heating the reaction medium.
One of the main advantages of this method is the ease of purifying formula XIII or XIV sulphonates by crystallization.
1.6 Conversion of intermediate IV or VI in which B represents a halogen or a sulphonate group into a formula I compound is brought about in conventional manner by reacting the intermediate with a carboxylic acid having the formula R.sub.5 --COOH, R.sub.5 having the previously-defined values, or with its metal salt or salt of addition with a nitrogenated organic or inorganic base such as an ammonium trialkylammonium salt or, depending on the nature of the R.sub.4 group, by reacting the intermediate with a phenol or phenolate having the formula R.sub.4 OH or R.sub.4 O.sup.-, R.sub.4 denoting a phenyl or substituted phenyl group as previously defined.
The reaction is brought about at a temperature between ambient temperature and the reflux temperature in a solvent such as acetone, water, a lower alcohol or pyridine, advantageously in the presence of an organic or inorganic base.
The reagents are normally used in stoichiometric quantities.
1.7 In a variant of the acylation process, in the case where, in the general formula I, R.sub.5 represents a radical --NH--R.sub.6 in which R.sub.6 has the previously-mentioned values, compounds VII and VIII can be converted into a formula I derivative by condensation with an isocyanate having the formula R.sub.6 --N.dbd.C.dbd.O (XV), as per diagrams 7a or 7b. ##STR14##
The reaction is brought about under anhydrous conditions by placing the reagents in an aprotic solvent having low polarity, e.g. an aliphatic or aromatic hydrocarbon or an ether or a polar solvent such as dimethylformamide or hexamethyl phosphortriamide.
When it is intended to prepare a mono-substituted compound I, a strictly metered quantity of isocyanate will be used.
To control the reaction more easily, the reagent is gradually added to the substrate, the reaction medium being cooled. At the end of the reaction it may be advantageous to heat the reaction mixture, if required to reflux, in order to complete the reaction.
2. In another method, formula I compounds can be obtained by substituting compound II or its alkali-metal salt by alkylation by an alkyl halide or sulphonate having the formula XVI (W--CHR.sub.3 --O--R.sub.4) in which R.sub.3 and R.sub.4 have the previously-defined values except that R.sub.4 does not denote hydrogen, and W represents an atom or group which is easily substitutable, e.g. chlorine, bromine, iodine or a sulphonate having the formula R.sub.12 --SO.sub.2 --O, R.sub.12 having the previously-specified values (see Section 1.5.2.).
This method is illustrated by diagrams 8a and 8b, in which M.sup.+ represents an alkali-metal cation. ##STR15##
The reaction is brought about by reacting an alkali-metal salt having the formula XVII or XVIII under anhydrous conditions with an alkylation agent having the formula XVI. It is performed in an aprotic polar solvent such as dimethylformamide or hexamethylphosphortriamide. Advantageously the reaction medium is heated for several hours, if required to reflux, in an inert anhydrous atmosphere to complete the reaction.
The amount of reagent XVI will depend on the nature of the salt (mono-salt formula XVII or di-salt formula XVIII), and it will advantageously be used in slight excess over the stoichiometric quantity.
The formula I reaction product is isolated by conventional methods, e.g. treatment of the reaction medium with water followed by filtration of compound I if solid or by extraction. The formula XVII and XVIII alkali metal salts are prepared in conventional manner by treatment of compound II under anhydrous conditions with a strong base in a suitable solvent, e.g. sodium or potassium hydroxide in a lower alcohol, a sodium or potassium alcoholate in an alcohol, or sodium hydride in an aliphatic hydrocarbon. The stoichiometry of the reagents used and their nature will determine the type of salt formed (mono-salt XVII or di-salt XVIII).
Although of use in preparing di-substituted formula I compounds, this method is particularly useful for synthesizing mono-substituted formula I compounds, since a formula XVII mono-salt is formed more easily than a formula XVIII di-salt.
2.1 In a variant, formula I compounds in which R.sub.1 and/or R.sub.2 represent a --CHR.sub.3 --O--CO--R.sub.5 group can be obtained by alkylation of compound II via salts XVII or XVIII, with an alpha-haloalkylether XIX; the formula XX or XXI intermediate ether formed is then converted to a formula I compound by a known method, e.g. by reaction with an anhydride having the formula (R.sub.5 CO).sub.2 O in which R.sub.5 represents an alkyl or cycloalkyl or substituted alkyl or phenyl group as previously defined, in the presence of a Lewis acid catalyst such as tin tetrachloride.
This variant is illustrated in diagrams 9a and 9b hereinafter, in which R.sub.5 has the values defined hereinbefore and M.sup.+ represents an alkali-metal cation. ##STR16##
Salts XVII or XVIII are alkylated under the same conditions as described for reagent XVI hereinbefore (see diagram 8a) and the intermediate formula XX or XXI ether is converted by agitating a solution or suspension of ether XX or XXI at ambient temperature under anhydrous conditions for several hours in an excess of anhydride (R.sub.5 CO).sub.2 O in the presence of the catalyst.
2.2 A variant of this method consists in converting ethers XX or XXI into a formula IV or VI derivative in which B represents a halogen such as chlorine or bromine, by treatment of ether with acetyl chloride in the presence of tin tetrachloride or with acetyl bromide in the presence of tin tetrabromide, under similar conditions to those described hereinbefore in Section 2.2.
The resulting formula IV or VI intermediates are then converted into formula I compound as described hereinbefore in Section 1.6.
This variant is illustrated in diagrams 10a and 10b. ##STR17##
3. In the formula I compounds according to the invention, groups R.sub.1 and R.sub.2 are not necessarily identical, and formula I compounds in which R.sub.1 and R.sub.2 are different can easily be prepared by suitably combining the previously-described methods.
By way of non-limitative example, a method of this kind is illustrated in diagram 11 hereinafter. ##STR18##
R.sub.3, R.sub.5, R.sub.6, W and M.sup.+ have the previously-given meanings except that groups R.sub.3 and R.sub.5 must not simultaneously have the same values in both substituents of the hydantoin nucleus.
The reaction conditions for these conversions are identical with those previously described for the same kind of reaction, except that care is taken that the reagents and reactions do not affect the other groups already present in the molecule.
4. The starting product for preparing the derivatives according to the invention, i.e. spiro/fluorene-9,4'-imidazolidine/-2',5'-dione (II) is very easily obtained by a conventional method /W. H. McCown, e.a., J. Am. Chem. Soc., 64, 689 (1942)/ starting from 9-fluoreneone, which is a commercial product, easily obtainable and easy to handle.
Note that the ease with which the products according to the invention can be synthesized distinguishes them from other similar products, e.g. those bearing a substituent on the fluorenyl group.